It is often the case that poorly water soluble pharmacological compounds are difficult to administer to living organisms in an effective manner because of one or more problems including poor bioavailability, too rapid decomposition and excretion, which creates a need for frequent re-dosing, and irritation or tissue damage at the location of introduction.
The bioavailability of poorly water soluble, orally administered drug is a major challenge for the pharmaceutical industry as many newly launched drugs possess low aqueous solubility, which leads to poor dissolution and low absorption. Furthermore, poor solubility results in variability in absorption and lack of dose proportionality. Compounding the problems of poor absorption is the problem that pharmacologically useful compounds may be substantially degraded in the gastrointestinal tract before absorption can occur. Solutions have been proposed including Self-Emulsifying Drug Delivery Systems (SEDDS's), defined as isotropic mixtures of one or more hydrophilic solvents and co-solvents/surfactants that are capable to form fine oil-in-water (o/w) emulsions upon mild agitation and dilution in gastrointestinal fluids, and various types of emulsions or suspensions.
Effective local anesthesia is required to minimize pain of minor cutaneous procedures on intact skin such as circumcision, cosmetic surgery, venipuncture, and laser procedures such as laser resurfacing and tattoo removal. Aromatic amide anesthetic compounds including lidocaine and prilocaine are preferred anesthetic drugs because of stability and low allergenicity. Lidocaine is the most widely used local anesthetic and is commonly provided in a topical form as a eutectic mixture with prilocaine, for example as EMLA™ cream, product of AstraZeneca.
Upon application of EMLA cream, a minimum of 60 minutes is required for onset of anesthesia for minor procedures and up to two hours for larger area skin grafts. Thus, the use of EMLA cream is inconvenient and impractical in clinical settings. The clinical utility of conventional creams such as EMLA is limited by diffusion across the stratum corneum, the outermost protective layer of skin. Liposomes (˜100 nm vesicles, composed of a lipid bilayer membrane surrounding an aqueous core) have been proposed as vehicles for transdermal delivery of drugs for over three decades, however, there are no liposomal drug forms approved by the US Food and Drug Administration for topical or dermal application.
It has been suggested to employ liposomes as carriers for topical anesthetics. Using the pin-prick assay, prolonged anesthesia and higher drug deposition in the epidermis and dermis after application from liposomal tetracaine and lidocaine have been reported. It would be desirable to have a dispersion of lipophilic particles as a cream or lotion product that provides rapid onset of anesthesia in addition to prolonged anesthesia and higher drug deposition, which may be provided by increasing dermal permeation of amide type anesthetics. Liposomal drug delivery has been considered to be a poor fit for delivery of hydrophobic drugs because of low entrapment efficiency. Hydrophobic compounds must exist in the hydrophobic galleries of liposomal lipid bilayers and typically only 1-2 mol % and rarely more than 5 mol % of hydrophobic drug can be incorporated into liposomes.